N-phenyl benzimidazolecarboxamide and N-phenyl indolecarboxamide derivatives

ABSTRACT

Disclosed are compounds of the forumla:                    
     or the pharmaceutically acceptable non-toxic salts thereof wherein; 
     A is N or CH; 
     R 1  and R 2  represents hydrogen or lower alkyl; 
     G, R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are variables defined herein. 
     These compounds are modulators of CRF receptors and are therefore useful for treating affective disorders, anxiety, depression, eating disorders, and stress disorders in humans and other animals. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. 
     Compounds of the invention are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

This application claims the benefit of U.S. Provisional Application no.60/127,624, filed Apr. 1, 1999.

FIELD OF THE INVENTION

This invention relates N-phenyl benzimidazolecarboxamides and N-phenylindolecarboxamides. When appropriately substituted, such compounds actas selective modulators of CRF1 receptors. This invention also relatesto pharmaceutical compositions comprising such compounds and to the useof such compounds in treatment of psychiatric disorders and neurologicaldiseases, including major depression, anxiety-related disorders,post-traumatic stress disorder, supranuclear palsy and feedingdisorders, as well as treatment of immunological, cardiovascular orheart-related diseases and colonic hypersensitivity associated withpsychopathological disturbance and stress. Additionally this inventionrelates to the use such compounds as probes for the localization of CRF1receptors in cells and tissues.

BACKGROUND

Corticotropin releasing factor (CRF), a 41 amino acid peptide, is theprimary physiological regulator of proopiomelanocortin (POMC) derivedpeptide secretion from the anterior pituitary gland. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain. There is alsoevidence that CRF plays a significant role in integrating the responseof the immune system to physiological, psychological, and immunologicalstressors.

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system.

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals. Furthermore, the density of CRF receptors is significantlydecreased in the frontal cortex of suicide victims, consistent with ahypersecretion of CRF. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (i.v. administered) observedin depressed patients. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression. There is also preliminary evidence that tricyclicantidepressants can alter CRF levels and thus modulate the numbers ofCRF receptors in brain.

CRF has also been implicated in the etiology of anxietyrelateddisorders. CRF produces anxiogenic effects in animals and interactionsbetween benzodiazepine/non-benzodiazepine anxiolytics and CRF have beendemonstrated in a variety of behavioral anxiety models. Preliminarystudies using the putative CRF receptor antagonist α-helical ovine CRF(9-41) in a variety of behavioral paradigms demonstrate that theantagonist produces “anxiolytic-like” effects that are qualitativelysimilar to the benzodiazepines. Neurochemical, endocrine and receptorbinding studies have all demonstrated interactions between CRF andbenzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test and in theacoustic startle test in rats. The benzodiazepine receptor antagonist Ro15-1788, which was without behavioral activity alone in the operantconflict test, reversed the effects of CRF in a dose-dependent manner,while the benzodiazepine inverse agonist FG 7142 enhanced the actions ofCRF.

CRF has also been implicated in the pathogeneisis of certainimmunological, cardiovascular or heart-related diseases such ashypertension, tachycardia and congestive heart failure, stroke andosteoporosis, as well as in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity associated with psychopathological disturbance andstress.

The mechanisms and sites of action through which conventionalanxiolytics and antidepressants produce their therapeutic effects remainto be fully elucidated. It has been hypothesized however, that they areinvolved in the suppression of CRF hypersecretion that is observed inthese disorders. Of particular interest are that preliminary studiesexamining the effects of a CRF receptor antagonist peptide (α-helicalCRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that theCRF antagonist produces “anxiolytic-like” effects qualitatively similarto the benzodiazepines.

SUMMARY OF THE INVENTION

The invention provides compounds of Formula I (shown below), andpharmaceutical compositions comprising compounds of Formula I. Suchcompounds bind to cell surface receptors, preferably G-coupled proteinreceptors, especially CRF receptors and most preferably CRF1 receptors.Preferred compounds of the invention exhibit high affinity for CRF 1receptors. Additionally, preferred compounds of the invention alsoexhibit high specificity for CRF1 receptors.

Preferred compounds of the present invention exhibit activity ascorticotropin releasing factor receptor antagonists and appear tosuppress the anxiogenic effects of CRF hypersecretion. The inventionalso provides methods of using compounds of Formula I for thesuppression of CRF hypersecretion and for the treatment of anxiogenicdisorders.

The invention further comprises methods of treating patients sufferingfrom certain disorders that are responsive to modulation of CRF1receptors with an effective amount of a compound of the invention. Thesedisorders include CNS disorders, particularly affective disorders,anxiety disorders, stress-related disorders, eating disorders andsubstance abuse. Treatment of human patients suffering from suchdisorders as well as other animals (domesticated companion animals(pets) or livestock animals in encompassed by the invention.

In another aspect, the invention provides pharmaceutical compositionscomprising compounds of Formula I or the pharmaceutically acceptablesalts or solvates thereof.

Additionally this invention relates to the use of the compounds of theinvention (particularly labeled compounds of this invention) as probesfor the localization of receptors in cells and tissues and as standardsand reagents for use in determining the receptor-binding characteristicsof test compounds. Labelled compounds of the invention may be used in invitro studies such as is autoradiography of tissue sections or for invivo methods, e.g. PET or SPECT scanning. Particularly, preferredcompounds of the invention are useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to theCRF1 receptor.

Accordingly, a broad aspect of the invention provides compounds ofgeneral Formula I:

or the pharmaceutically acceptable non-toxic salts thereof wherein:

A represents N or C—Y, where Y is hydrogen or (C₁-C₆)alkyl;

G represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy,nitrile, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio-, thio(C₁-C₆)alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl;

R₁ represents hydrogen, (C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl;

R₂ represents hydrogen or (C₁-C₆)alkyl, with the proviso that R₂ ishydrogen when A is C—Y;

R₃ and R₄ are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆) alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl,—SH, (C₁-C₆)alkylthio, thio(C₁-C₆) alkyl or (C₁-C₆)alkylthio(C₁-C₆)alkyl; and

R₅, R₆, R₇ and₈ are the same or different and represent hydrogen,halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆) alkoxy, hydroxy(C₁-C₆)alkoxy,hydroxy, hydroxy(C₁-C₆) alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, amino,mono- or dialkylamino, (C₁-C₆)alkylthio, thio(C₁-C₆)alkyl or (C₁-C₆)alkyl thio(C₁—C₆)alkyl.

In another aspect, the invention provides methods for treating and/orpreventing the above-listed disorders, which methods compriseadministration to a patient of an effective amount of a compound ofFormula I.

In yet another aspect, the invention provides intermediates useful inthe preparation of the compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of Formula I

include those compounds, or the pharmaceutically acceptable non-toxicsalts thereof wherein:

A represents N or C—Y, where Y is hydrogen or (C₁-C₆)alkyl;

G represents halogen, trifluoromethyl, trifluoromethoxy, nitrile,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio-, thio(C₁-C₆) alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl;

R₁ represents hydrogen, (C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl;

R₂ represents hydrogen or (C₁-C₆)alkyl, with the proviso that R₂ ishydrogen when A is C—Y;

R₃ and R₄ are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆) alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy,hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl, —SH,(C₁-C₆)alkylthio, thio(C₁-C₆) alkyl or (C₁-C₆)alkyl thio(C₁-C₆)alkyl,with the proviso that R₃ and R₄ cannot both be hydrogen simultaneously;and

R₅,R₆, R₇ and R₈ are the same or different and represent hydrogen,halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆) alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,—SH, (C₁-C₆)alkylthio, thio(C₁-C₆)alkyl or (C₁-C₆)alkylthio(C₁-C₆)alkyl.

The compounds of the instant invention are represented by the generalFormula I set forth above and include pharmaceutically acceptablenon-toxic salts thereof.

Preferred compounds of Formula I are those where R₁ is a C₁-C4 group,more preferably a C₂-C₄ group, and most preferably an isopropyl group.Other preferred compounds of Formula I include those where R₂ ishydrogen or C₁-C₃ alkyl, preferably methyl. More preferred compounds ofFormula I include those where R₁ is a C₂-C₄ group, most preferably anisopropyl group, and R₂ is hydrogen or C₁-C₃ alkyl, preferably methyl.

Particularly preferred compounds of Formula I are those where G ismethyl and R₇ and R₈ are in the 4- and 6-positions on the phenyl ringrespectively and independently represent hydrogen, C₁-C₂ alkoxy, C₁-C₆alkyl, halogen, or trifluoromethyl.

Preferred

groups in Formula I include 2-, 3-, or 4-(C₁-C₆)alkoxyphenyl, ₄-(C₁-C₆)alkoxy-2-(C₁-C₆)alkylphenyl, 2-, 3-, or 4-(C₁-C₆)al phenyl, 2- or4-halophenyl, 4-hydroxyphenyl, and 4-hydroxy-2-(C₁-C₆)alkylphenyl.

Particularly preferred

groups in Formula I include (4-methoxy-2-methylphenyl), 4-methoxyphenyl,3-methoxyphenyl, 3-methylphenyl, 2-methoxyphenyl,4-chloro-2-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 4-fluorophenyl,4-chlorophenyl, 4-hydroxyphenyl, _(2,4)-dimethylphenyl, 4-ethoxyphenyl,4-hydroxy-2-methylphenyl, 3-hydroxy-4-methoxyphenyl.

In preferred compounds of Formula I, R₅, and R₆ are at the 5-and6-positions of the benzimidazole or indole ring system and representhydrogen, fluoro, chloro, bromo, C₁-C₆ alkoxy, more preferably methoxyor ethoxy, or C₁-C₆ alkyl, more preferably methyl or ethyl. Particularlypreferred are compounds of Formula I where one of R₅ and R₆ is hydrogenand the other is hydrogen, fluoro, chloro, methoxy, ethoxy, methyl orethyl.

Other preferred compounds of invention are encompassed by Formula II.

wherein

R₁ is as defined above for Formula I;

Q is

G represents halogen, trifluoromethyl, trifluoromethoxy, nitrile,(C₁-C₆)alkyl, (C₁-C₆) alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio, thio(C₁-C₆) alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl;

R₂ represents hydrogen or (C₁-C₆)alkyl,

R₃ and R₄ are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆) alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl,thiol, (C₁-C₆)alkylthiol, thio(C₁-C₆) alkyl or (C₁-C₆)alkylthio(C₁-C₆)alkyl, with the proviso that R₃ and R₄ cannot both behydrogen; and

R₅, R₆, R₇ and R₈, are the same or different and represent hydrogen,halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆) alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,thiol, (C₁-C₆) alkylthiol, thio(C₁-C₆)alkyl or (C₁-C₆)alkyl thio(C₁-₂₀C₆)alkyl.

Other preferred compounds of Formula II are those where R₅ and R₆independently represent hydrogen, halogen, more preferably chloro orfluoro, hydroxy, trifluoromethyl, nitrile, C₁-C₃ alkyl, more preferablymethyl, or C₁-C₃ alkoxy, more preferably methoxy or ethoxy.

Yet other preferred compounds of Formula II are those where G is C₁-C₃alkyl, C₁-C₃ alkoxy, or halogen.

Still other preferred compounds of II include those where R₅ and R₆ arehydrogen and G is methyl, methoxy, or chloro. More preferred compoundsof Formula II include those where R₅ and R₆ are hydrogen; G is methyl,methoxy, or chloro; and R₇ and R₈ are independently hydrogen, C₁-C₆alkoxy, C₁-C₆ alkyl, halogen, or trifluoromethyl.

Particularly preferred compounds of Formula II are those where Q is

where G is C₁-C₂ alkyl and R₇ and R₈ are independently hydrogen, C₁-C₂alkoxy, C₁-C₂ alkyl, halogen, or trifluoromethyl. Still otherparticularly preferred compounds of Formula II include those where R₅and R₆ are hydrogen; G is methyl, methoxy, or chloro; and R₇ and R₈ areindependently hydrogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halogen, ortrifluoromethyl. In highly preferred embodiments of Formula II, Q istrimethylphenyl.

Other preferred compounds of Formula II include those where R₁ is C₂-C₄alkyl, more preferably isopropyl. Yet other preferred compounds ofFormula II include those where R₂ is hydrogen.

In other preferred compounds of Formula II, R₅ and R₆ are at the 5- and6-positions of the benzimidazole or indole ring system and representhydrogen, fluoro, chloro, bromo, C₁-C₆ alkoxy, more preferably methoxyor ethoxy, or C₁-C₆ alkyl, more preferably methyl or ethyl. Other morepreferred are compounds of Formula II where one of R₅ and R₆ is hydrogenand the other is hydrogen, fluoro, chloro, methoxy, ethoxy, methyl orethyl.

In addition, the invention encompasses compounds of Formula III

wherein R₁ is as defined above for Formula I. represents

G represents halogen, trifluoromethyl, trifluoromethoxy, nitrile,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio, thio(C₁-C₆) alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl;

R₁ represents hydrogen or (C₁-C₆)alkyl;

R₃ and R₄ are same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆) alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl,thio, (C₁-C₆)alkylthiol, thio(C₁-C₆) alkyl or (C₁-C₆)alkylthio(C₁-C₆)alkyl, with the proviso that R₃ and R₄ cannot both behydrogen simultaneously; and

R₅, R₆, R₇ and R₈ are the same or different and represent hydrogen,halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆) alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,—SH, (C₁-C₆)alkylthiol, thio(C₁-C₆)alkyl or (C₁-C₆)alkylthio(C₁-C₆)alkyl.

Preferred compounds of Formula III are those where R₅ and R₆independently represent hydrogen, halogen, more preferably chloro orfluoro, hydroxy, trifluoromethyl, nitrile, C₁-C₃ alkyl, more preferablymethyl, or C₁-C₃ alkoxy, more preferably methoxy or ethoxy.

Yet other preferred compounds of Formula III are those where G is C₁-C₃alkyl, C₁-C₃ alkoxy, or halogen.

Still other preferred compounds of III include those where R₅ and R₆ arehydrogen and G is methyl, methoxy, or chloro. More preferred compoundsof Formula III include those where R₅ and R₆ are hydrogen; G is methyl,methoxy, or chloro; and R₇ and R₈ are independently hydrogen, C₁-C₆alkoxy, C₁-C₆ alkyl, halogen, or trifluoromethyl.

Particularly preferred compounds of Formula III are those where Q is

where G is C₁-C₂ alkyl and R₇ and R₈ are independently hydrogen, C₁-C₂alkoxy, C₁-C₂ alkyl, halogen, or trifluoromethyl. Still otherparticularly preferred compounds of Formula III include those where R₅and R₆ are hydrogen; G is methyl, methoxy, or chloro; and R₇ and R₈ areindependently hydrogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halogen, ortrifluoromethyl. In highly preferred embodiments of Formula III, Q istrimethylphenyl.

Other preferred compounds of Formula III include those where R₁ is C₂-C₄alkyl, more preferably isopropyl.

In other preferred compounds of Formula III, R₅ and R₆ are at the 5- and6-positions of the benzimidazole or indole ring system and representhydrogen, fluoro, chloro, bromo, C₁-C₆ alkoxy, more preferably methoxyor ethoxy, or C₁-C₆ alkyl, more preferably methyl or ethyl. Other morepreferred are compounds of Formula III where one of R₅ and R₆ ishydrogen and the other is hydrogen, fluoro, chloro, methoxy, ethoxy,methyl or ethyl.

Compounds of the invention are useful in treating a variety ofconditions including affective disorders, anxiety disorders, stressdisorders, eating disorders, and drug addiction.

Affective disorders include all types of depression, bipolar disorder,cyclothymia, and dysthymia.

Anxiety disorders include generalized anxiety disorder, panic, phobiasand obsessive-compulsive disorder.

Stress-related disorders include post-traumatic stress disorder,hemorrhagic stress, stress-induced psychotic episodes, psychosocialdwarfism, stress headaches, stress-induced immune systems disorders suchas stress-induced fever, and stress-related sleep disorders.

Eating disorders include anorexia nervosa, bulimia nervosa, and obesity.

Modulators of the CRF receptors may also be useful in the treatment of avariety of neurological disorders including supranuclear palsy, AIDSrelated dementias, multiinfarct dementia, neurodegenerative disorderssuch as Alzheimer's disease, Parkinson's disease, and Huntington'sdisease, head trauma, spinal cord trauma, ischemic neuronal damage,amyotrophic lateral sclerosis, disorders of pain perception such asfibromyalgia and epilepsy.

Additionally compounds of Formula I are useful as modulators of the CRFreceptor in the treatment of a number of gastrointestestinal,cardiovascular, hormonal, autoimmune and inflammatory conditions. Suchconditions include irritable bowel syndrome, ulcers, Crohn's disease,spastic colon, diarrhea, post operative ilius and colonichypersensitivity associated with psychopathological disturbances orstress, hypertension, tachycardia, congestive heart failure,infertility, euthyroid sick syndrome, inflammatory conditions effectedby rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis andallergies.

Compounds of Formula I are also useful as modulators of the CRF₁receptor in the treatment of animal disorders associated with aberrantCRF levels. These conditions include porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, and dysfunctions inducedby confinement in chickens, sheering stress in sheep or human-animalinteraction related stress in dogs, psychosocial dwarfism andhypoglycemia.

By “alkyl”, “lower alkyl”, and “(C₁-C₆)alkyl” in the present inventionis meant straight or branched chain alkyl groups or cycloalkyl groupshaving 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl, cyclopropyl, andcyclopropylmethyl.

By “alkoxy”, “lower alkoxy”, and “(C₁-C₆)alkoxy” in the presentinvention is meant straight or branched chain alkoxy groups having 1-6carbon atoms, such as, for example, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

Representative compound of the invention are shown below in Table 1

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds described inthe Examples and their pharmaceutically acceptable acid addition salts.In addition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n-COOH where n is0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

The invention encompasses all possible tautomers and rotamers of thecompounds represented by Formula I.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Composition intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most CNSdisorders, a dosage regimen of 4 times daily or less is preferred. Forthe treatment of stress and depression a dosage regimen of 1 or 2 timesdaily is particularly preferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding and desirablein vitro and in vivo half-lifes. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat periphereal disorders are oftenpreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lifes of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

The present invention also pertains to packaged pharmaceuticalcompositions for treating disorders responsive to C5a receptormodulation, e.g., eating disorders, depression or stress. The packagedpharmaceutical compositions include a container holding atherapeutically effective amount of at least one CRF1 receptor modulatoras described supra and instructions for using the treating disorderresponsive to CRF1 receptor modulation in the patient.

Compounds of the invention can be prepared using the reactions depictedin Schemes I to III. In Schemes I-III, the groups G, R₁, R₂, R₃, R₄, R₅,R₆, R₇, R₈ and Y are as defined in general Formula I.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

Commercial reagents were used without further purification. Roomtemperature refers to 20 to 25° C. TLC refers to thin layerchromatography. Mass spectral data were obtained either by ESI or APCImethods.

EXAMPLE 1 General Procedure for the Preparation ofChloromethylbenzimidazoles as Outlined in Scheme I

1. Imidate hydrochloride:

A solution of 150 mL (2.37 mole) of chloroacetonitrile, 139 mL (2.37mole) of ethanol in 1,200 mL of dry benzene is cooled to 0° C. in anice/ethanol bath. Dry HCl gas is bubbled through the vigorously stirredsolution for approximately 30 minutes while the internal temperature ismaintained below 10° C. The solution is allowed to stand at roomtemperature overnight. The resulting solid is filtered and washed with2L of dry ether and allowed to air dry to afford 328 g (88%) of imidatehydrochloride.

2. 1-[2-(chloromethyl)benzimidazolyl]-4-methoxy-2-methylbenzene:

Diarylamines were prepared according to literature procedure [J. J.Kulagowski and C. W. Rees, Synthesis, 215 (1980)]. A solution of 60 g(0.26 mole) of (2-aminophenyl) (4-methoxy-2-methylphenyl) amine in 350mL of anhydrous chloroform is treated with 59 g (0.37 mole) of imidateat room temperature. The heterogeneous reaction mixture is allowed tostir for 1 hour at room temperature at which time no starting materialis detectable by TLC. 100 mL of saturated NaHCO₃ is added and extractedwith 4 X 150 mL of CH₂Cl₂. The extracts are dried over anhydrous Na₂SO₄,the solvent removed in vacuo, and the residue chromatgraphed (SiO₂) with20% ethyl acetate/hexane to afford 50 g (65%) of1-[2-(chloromethyl)benzimidazolyl]-4-methoxy-2-methylbenzene: Mass Spec.287 (M+H).

EXAMPLE 2

General Procedure for the Preparation of Benzimidazole Carboxamides asShown in Scheme II

N-{[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide

A solution of 3 g (10.5 mmole) 1-[2-(chloromethyl)benzimidazolyl]-4-methoxy-2-methylbenzene in 20 mL of dry acetonitrileis treated with 5 mL of isopropylamine for 1 hour in a sealed reactionvessel at 50° C. The solvent is removed in vacuo and the residue ispartitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. Theethyl acetate layer is dried over anhydrous Na₂SO₄ and solvent removedin vacuo to afford 3.1 g (98%){([1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}(methylethyl)amine. The latter amine is then vigorously stirred with 2.6 mL of2,4,6-trimethylbenzoylchloride in a 1:1 mixture of dichloroethane andsaturated aqueous sodium carbonate (30 mL) at room temperature for 1hour. The mixture is partitioned, the organic layer is dried with Na₂SO₄and the solvent removed in vacuo. The crystallized product is trituratedin ethyl ether, filtered and dried to afford 4.4 g (92%) of white solidN-{[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: Mass Spec. 456 (M+H); (Compound 1).

EXAMPLE 3

The following compounds are prepared essentially as described inExamples 1 and 2 and as shown in Schemes I and II.

a) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trichlorophenyl)carboxamide: MS 502 (M+H) (Compound 2).

b) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2-methylphenyl)carboxamide: MS 414 (M+H); (Compound 3).

c) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4-dimethylphenyl)carboxamide: MS 428 (M+H); (Compound 4).

d) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2-methoxyphenyl)carboxamide: MS 430 (M+H); (Compound 5).

e) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(3-fluoro-2-methylphenyl)carboxamide: MS 432 (M+H); (Compound 6).

f) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2-methoxyphenyl)carboxamide: MS 464 (M+H); (Compound 7).

g) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4-dichlorophenyl)carboxamide: MS 468 (M+H); (Compound 8).

h) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethylphenyl)carboxamide: MS 428 (M+H); (Compound 9).

i) N-{[1-(3-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 442 (M+H); (Compound 10).

j) N-{[1-(3-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 426 (M+H); (Compound 11).

k) N-{[1-(2-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 442 (M+H); (Compound 12).

l) N-{[1-(2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 426 (M+H) (Compound 13).

m)N-{[1-(4-chloro-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 461 (M+H); (Compound 14).

n) N-{[1-(4-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 426 (M+H) (Compound 15).

o) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 442 (M+H); (Compound 16).

p) N-{[1-(2-chlorophenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 446 (M+H); (Compound 17).

q) N-{[1-(4-fluorophenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 430 (M+H) (Compound 18).

r) N-{[1-(4-chlorophenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 446 (M+H); (Compound 19).

s) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2-fluoro-4-trifluoromethylphenyl)carboxamide: MS 486 (M+H); (Compound20).

t) N-{[1-(4-hydroxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 428 (M+H) (Compound 21).

u)N-{[5-fluoro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 460 (M+H); (Compound 22).

v)N-{[6-methoxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 472 (M+H); (Compound 23).

w)N-{[6-ethoxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 486 (M+H); (Compound 24).

x)N-{[6-chloro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 477 (M+H); (Compound 25).

y)N-{[1-(4-methoxyphenyl)-5-methylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 456 (M+H); (Compound 26).

z) N-{[1-(2,4-dimethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 440 (M+H) (Compound 27).

aa) N-{[1-(4-ethoxyphenyl)benzimidazol-2-y]methyl}-N-(methylethyl) (2,4, 6-trimethylphenyl)carboxamide: MS 456 (M+H) (Compound 28).

bb)N-{[1-(4-hydroxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 442 (M+H); (Compound 29).

cc)N-{[1-(3-hydroxy-4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 458 (M+H); (Compound 30).

dd) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide: MS 458 (M+H); (Compound 31).

ee)N-{[5-fluoro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide: MS 476 (M+H); (Compound 32).

ff)N-{[1-(4-methoxyphenyl)-5-methylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide: MS 472 (M+H); (Compound 33).

gg) N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 412 (M+H); (Compound 34).

hh) N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl)(2,4,6-trichlorophenyl)carboxamide: MS 472 (M+H); (Compound 35).

ii) N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl)(2,4-dimethylphenyl)carboxamide: MS 398 (M+H); (Compound 36).

jj)N-{[1-(2,4,6-trimethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 454 (M+H); (Compound 37).

kk)N-{[1-(2,4,6-trimethylphenyl)benzimidazol-2-yl]methyl}-N-(cyclopropyl)(2,4,6-trimethylphenyl)carboxamide: MS 452 (M+H); (Compound 38).

ll) N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(cyclopropyl) (2,4-dimethylphenyl)carboxamide: MS 410 (M+H); (Compound 39).

mm) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-trifluoromethylphenyl)carboxamide: MS 466 (M+H); (Compound 40).

nn) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(dimethylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 456 (M+H); (Compound 41)

oo)N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}(2,4,6-trimethylphenyl)carboxamide: MS 400 (M+H); (Compound 42).

pp)N-{[1-(4-(2-hydroxyethoxy)phenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 472 (M+H); (Compound 43).

qq)N-{[6-hydroxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 458 (M+H); (Compound 44).

rr)N-{[6-chloro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide: MS 492 (M+H); (Compound 45).

ss) N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2,6-dimethylphenyl)carboxamide: MS 462 (M+H); (Compound 46).

tt)N-{[5-methyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2,6-dimethylphenyl)carboxamide: MS 476 (M+H); (Compound 47).

uu)N-{[5-methyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-methoxy-2-methylphenyl)carboxamide: MS 458 (M+H); (Compound 48).

vv)N-{[5-bromo-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 520 (M+H); (Compound 49).

ww)N-{[1-(4-fluoro-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 444 (M+H); (Compound 50).

xx)N-{[1-(4-methoxy-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 524 (M+H); (Compound 51).

yy)N-{[5-tert-butoxycarbamyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 557 (M+H); (Compound 52).

zz)N-{[5-amino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 457 (M+H); (Compound 53).

aaa)N-{[5-dimethylamino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 485 (M+H); (Compound 54).

bbb)N-{[5-methyl-1-(4-trifluoromethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 494 (M+H); (Compound 55).

ccc)N-{[5-methyl-1-(4-trifluoromethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2,6-dimethylphenyl)carboxamide: MS 514 (M+H); (Compound 56).

ddd) N-{[1-(4-hydroxy-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide:MS 510 (M+H); (Compound 57).

eee)N-{[1-(4-(2-hydroxyethoxy)-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 554(M+H); (Compound 58).

fff)N-{[1(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(4-dimethylamino-2,6-dimethylphenyl)carboxamide: MS 539 (M+H); (Compound59).

ggg)N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(4-hydroxy-2,6-dimethylphenyl)carboxamide: MS 512 (M+H); (Compound 60).

hhh)N-{[5-diethylamino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 513 (M+H); (Compound 61).

iii)N-{[1-(4-(2-hydroxyethoxy)-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 486 (M+H); (Compound 62).

jjj)N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-[1-(hydroxymethyl)ethyl](2,4,6-trimethylphenyl)carboxamide: MS 526 (M+H); (Compound 63).

kkk) N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(3-hydroxypropyl)(2,4,6-trimethylphenyl)carboxamide: MS 526 (M+H); (Compound 64).

lll) N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-[2-hydroxy-1-(hydroxymethyl)ethyl](2,4,6-trimethylphenyl)carboxamide: MS 542 (M+H); (Compound 65).

mmm)N-{[(5-iodo-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 568 (M+H); (Compound 66).

nnn) N-{[1-(4-hydroxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: MS 496 (M+H); (Compound 67).

EXAMPLE 4

General Procedure for the Preparation of Indole Carboxamides as Shown inScheme III

N-{[1-(4-methoxyphenyl)indol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide

N-Phenyl indolecarboxylic acids are prepared according to literatureprocedures [P.C. Unangst et al., J. Heterocyclic Chem., 24, 811 (1987)].To a solution of the N-(4-methoxy) phenylindole-2-carboxylic acid (2 g,7.48 mmol) in N,N-dimethylformamide (15 ml) is added triethylamine (1.25ml, 9 mmol) followed by diethyl cyanophosphonate (DECP) (1.52 ml, 9mmol) at 0° C. The resulting solution is stirred for 10 minutes beforeisopropylamine (1.92 ml, 22.5 mmol) is added. After stirring at roomtemperature for 1 hour, the solution is diluted with water and extractedwith ethyl acetate. The extracts are combined, washed with water, washedwith brine and then dried. Solvent is removed in vacuo to give theproduct as a light yellow solid (2.07 g, 90%).

A mixture of the latter amide (840 mg, 2.72 mmol) in tetrahydrofuran(THF, 4 mL) is added to a solution of lithium aluminum hydride in THF(1N, 6.8 ml). The resulting yellow solution is refluxed for 24 hours andthen cooled to room temperature, diluted with Et₂O and quenched byadding water at 0° C. until formation of a gel. The Et₂O layer isseparated and the gel is extracted with more Et₂O. The combined Et₂Oextract is washed with water, washed with brine and dried. Solvent isremoved in vacuo to give a yellow oil residue that is stirred in 1N HCl(5 ml) and Et₂O (10 ml). The white precipitate is separated, washed withwater, rinsed with Et₂O and dried to give the product as itshydrochloride (430 mg, 48%).

To the latter amine (165 mg, 0.5 mmol) in dichloroethane (2 ml) andtriethylamine (0.25 ml, 1.75 mmol) is added 2,4,6-trimethylbenzoylchloride (0.166 ml, 1 mmol). The resulting mixture is stirred at roomtemperature for 4 hours, diluted with CH₂Cl₂, washed with water, washedwith saturated aqueous NaHCO₃ solution, washed with brine and dried. Thesolvent is removed in vacuo and the residue is purified by silica gelcolumn (CH₂Cl₂ elution) to give a white solid (100 mg) ofN-{[1-(4-methoxyphenyl)indol-2-yl]methyl}-N-(methylethyl)(_(2,4,6)-trimethylphenyl)carboxamide: MS 441 (M+H); (Compound 68).

EXAMPLE 5 Assay for CRF Receptor Binding Activity

The following two assays for human CRF1 receptor activity are standardassays of CRF binding that may be used to determine the affinity of CRFfor the CRF receptor.

Assay for Recombinant Human CRF₁ Receptor Binding Activity

CRF receptor binding is performed using a modified version of the assaydescribed by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5,1991). Membrane pellets containing CRF receptors are re-suspended in 50mM Tris buffer pH 7.7 containing 10 mM MgCl₂ and 2 mM EDTA andcentrifuged for 10 minutes at 48000 g. Membranes are washed again andbrought to a final concentration of 1500 mg/ml in binding buffer (Trisbuffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg/mL aprotinin.).For the binding assay, 100 mL of the membrane preparation is added to 96well microtube plates containing 100 mL of ¹²⁵I-CRF (SA 2200 Ci/mmol,final concentration of 100 pM) and 50 mL of drug. Binding is carried outat room temperature for 2 hours. Plates are then harvested on a Brandel96 well cell harvester and filters are counted for gamma emissions on aWallac 1205 Betaplate liquid scintillation counter. Non specific bindingis defined by 1 mM cold CRF. IC₅₀ values are calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass.). The binding affinity for the compounds of Formula Iexpressed as IC₅₀ value, generally ranges from about 0.5 nanomolar toabout 10 micromolar.

Preferred Arylpyrimidines of the invention exhibit good activity instandard in vitro receptor binding assays, specifically the assay asspecified in Example 44, which follows and is defined below.Particularly preferred arylpyrimidines of the invention have an IC₅₀ ofabout 10 micromolar or less, still more preferably and IC₅₀ of about 100nanomolar or less even more preferably an IC₅₀ of about 10 nanomolar orless or even 1 nanomolare or less in such a defined standard in vitroCRF receptor binding assay.

Alternatively, the binding activity of the compounds of formula I to thehuman CRF₁ receptor can be measured as follows:

Assay for Human CRF Receptor Binding Activity in IMR32 cells

IMR-32 human neuroblastoma cells are grown to 80% confluence in EMEMcontaining Earle's Balanced Salts and 2 mM 1-glutamine with 10% FBS, 25mM HEPES, 1 mM Sodium Pyruvate, and nonessential amino acids. At thistime, flasks of cells are treated with 2.5 uM 5-bromo-2′-deoxyuridine(Br-dU) for 10 days. Media is changed every 3-4 days across the 10-dayperiod. Cells are harvested using No-Zyme (JRH Biosciences) and rinsedwith PBS. For membrane preparation, cells are homogenized in wash buffer(50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4) and centrifuged at48,000×g for 10 minutes at 4° C. Pellets are resuspended, homogenizedand centrifuged two additional times. The receptor binding assay isperformed using assay buffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH7.4, 0.1% BSA, 0.1 mM bacitracin (22.0 mg/100 mL)), 150 ug protein/tube,and [¹²⁵I] Sauvagine (NEN; 100 pM for competition analysis and 10 pM-1nM for saturation analysis) to yield a final volume of 200 uL.Nonspecific binding is defined using 2 uM r/h CRF or 9-41 alpha-helicalCRF. Cells are incubated for 2 hours at room temperature. The assay isterminated by rapid vacuum filtration (Tomtec: Deepwell 3) through GFCfilters presoaked in 1% PEI using ice-cold 50 mM Tris Hcl and drythoroughly by air. Specific Binding: 70-80%; Kd (nM): 0.30 nM; Bmax(fmole/mg protein): 40-50. IC₅₀ values are calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass.). The binding affinities for the compounds of Formula Iexpressed as IC₅₀ value are less than 10 micromolar.

EXAMPLE 6 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

EXAMPLE 7 Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExample.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable non-toxic salt thereof wherein: Arepresents N; G represents halogen, trifluoromethyl, trifluoromethoxy,cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆) alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio-, thio (C₁-C₆)alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl; R₁ represents hydrogen, (C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₂ represents hydrogen or (C₁-C₆)alkyl; and R₃, andR₄ are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH,(C₁-C₆)alkylthio, thio(C₁-C₆) alkyl or (C₁-C₆)alkyl thio(C₁-C₆)alkyl;R₅, R₆, R₇ and R₈ are the same or different and represent hydrogen,halogen, trifluoromethyl, trifluoromethoxy, cyano, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy,hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl, —SH,(C₁-C₆)alkylthio, thio(C₁-C₆)alkyl or (C₁-C₆)alkyl thio(C₁-C₆)alkyl. 2.A compound of the formula:

or a pharmaceutically acceptable non-toxic salt thereof wherein: Arepresents N; G represents halogen, trifluoromethyl, trifluoromethoxy,cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆) alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio-, thio(C₁-C₆)alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl; R₁ represents hydrogen, (C₁-C₆)alkyl orhydroxy(C₁-C₆)alkyl; R₂ represents hydrogen or (C₁-C₆)alkyl; R₃ and R₄are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy, hydroxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio,thio(C₁-C₆)alkyl or (C₁-C₆)alkyl thio(C₁-C₆)alkyl, with the proviso thatR₃ and R₄ cannot both be hydrogen simultaneously; and R₅, R₆, R₇ and R₈are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy, hydroxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio,thio(C₁-C₆)alkyl or (C₁-C₆)alkyl thio(C₁-C₆)alkyl.
 3. A compound of theformula:

or a pharmaceutically acceptable non-toxic salt thereof wherein: Qrepresents

G represents halogen, trifluoromethyl, trifluoromethoxy, cyano,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆) alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SH, (C₁-C₆)alkylthio, thio(C₁-C₆)alkyl or(C₁-C₆)alkyl thio(C₁-C₆)alkyl; R₁ represents hydrogen or (C₁-C₆)alkyl;R₂ represents hydrogen or (C₁-C₆)alkyl; R₃ and R₄ are the same ordifferent and represent hydrogen, halogen, trifluoromethyl,trifluoromethoxy, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, thiol,(C₁-C₆)alkylthiol, thio(C₁-C₆) alkyl or (C₁-C₆)alkyl thio(C₁-C₆)alkyl,with the proviso that R₃ and R₄ cannot both be hydrogen; and R₅, R₆, R₇and R₈ are the same or different and represent hydrogen, halogen,trifluoromethyl, trifluoromethoxy, nitrile, (C₁-C₆) alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆) alkoxy(C₁-C₆)alkyl,thiol, (C₁-C₆)alkylthiol, thio(C₁-C₆) alkyl or (C₁-C₆)alkylthio(C₁-C₆)alkyl.
 4. A compound according to claim 2, wherein R₅ and R₆independently represent hydrogen, halogen, hydroxy, trifluoromethyl,cyano, C₁-C₃ alkyl, or C₁-C₃ alkoxy.
 5. A compound according to claim 3,wherein R₅ and R₆ independently represent hydrogen, fluoro, chloro,hydroxy, trifluoromethyl, or methyl.
 6. A compound according to claim 4,wherein G is C₁-C₃ alkyl, C₁-C₃ alkoxy, or halogen.
 7. A compoundaccording to claim 4, wherein R₅ and R₆ are in the 5-and 6-positionrespectively and independently represent hydrogen, fluoro, chloro,methyl, ethyl, ethoxy or methoxy, and G is methyl, methoxy, or chloro.8. A compound according to claim 5, wherein R₇ and R₈ are independentlyhydrogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halogen, or trifluoromethyl.
 9. Acompound according to claim 4 where Q is

where G is C₁-C₂ alkyl and R₇ and R₈ are independently hydrogen, C₁-C₂alkoxy, C₁-C₂ alkyl, halogen, or trifluoromethyl.
 10. A compoundaccording to claim 2, wherein Q is trimethylphenyl.
 11. A compoundaccording to claim 6, wherein Q is trimethylphenyl.
 12. A compoundaccording to claim 4, wherein R₁ is C₂-C₄ alkyl.
 13. A compoundaccording to claim 6, wherein R₁ is C₂-C₃ alkyl.
 14. A compoundaccording to claim 2, where R₁ is isopropyl.
 15. A compound according toclaim 8, wherein R₁ is isopropyl.
 16. A compound according to claim 12,wherein R₂ is hydrogen.
 17. A compound according to claim 13, wherein R₂is hydrogen.
 18. A compound according to claim 1, which isN-{[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 19. A compound according to claim 1,which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trichlorophenyl)carboxamide.20. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2-methylphenyl)carboxamide.21. A compound according to claim 1, which is N-{[1-(4-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4-dimethylphenyl)carboxamide.22. A compound according to claim 1, which is N-{[1-(4-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2-methoxyphenyl)carboxamide.23. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(3-fluoro-2-methylphenyl)carboxamide.24. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2-methoxyphenyl)carboxamide.25. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4-dichlorophenyl)carboxamide.26. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethylphenyl)carboxamide.27. A compound according to claim 1, which is N-{[1-(3-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 28. A compound according to claim 1,which is N-{[1-(3-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 29. A compound according to claim 1,which is N-{([1-(2-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.30. A compound according to claim 1, which is N-{[1-(2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.31. A compound according to claim 1, which isN-{[1-(4-chloro-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.32. A compound according to claim 1, which is N-{[1-(4-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.33. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.34. A compound according to claim 1, which is N-{[1-(2-chlorophenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 35. A compound according to claim 1,which is N-{[1-(4-fluorophenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.36. A compound according to claim 1, which is N-{[1-(4-chlorophenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.37. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2-fluoro-4-trifluoromethylphenyl)carboxamide.38. A compound according to claim 1, which is N-{([l-(4-hydroxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.39. A compound according to claim 1, which isN-{[5-fluoro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.40. A compound according to claim 1, which isN-{[6-methoxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 41. A compound according to claim 1,which is N-{[6-ethoxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.42. A compound according to claim 1, which isN-{[6-chloro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.43. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)-5-methylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 44. A compound according to claim 1,which is N-{[1-(2,4-dimethylphenyl)benzimidazol-2-yl]methyl)}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.45. A compound according to claim 1, which is N-{[1-(4-ethoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.46. A compound according to claim 1, which isN-{[1-(4-hydroxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.47. A compound according to claim 1, which isN-{[1-(3-hydroxy-4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.48. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide.49. A compound according to claim 1, which isN-{[5-fluoro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide.50. A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)-5-methylbenzimidazol-2-yl]methyl)-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide.51. A compound according to claim 1, which is selected from:N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl)(2,4,6-trimethylphenyl) carboxamide;N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl)(2,4,6-trimethylphenyl) carboxamide;N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl)(2,4,6-trimethylphenyl) carboxamide;N-{[1-(2,4,6-trimethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl) carboxamide;N-{[1-(2,4,6-trimethylphenyl)benzimidazol-2-yl]methyl}-N-(cyclopropyl)(2,4,6-trimethylphenyl)carboxamide;N-[(i-phenylbenzimidazol-2-yl)methyl]-N-(cyclopropyl)(2,4-dimethylphenyl)carboxamide;N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-trifluoromethylphenyl)carboxamide;N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(dimethylethyl)(2,4,6-trimethylphenyl)carboxamide;N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}(2,4,6-trimethylphenyl)carboxamide;N-{[1-(4-(2-hydroxyethoxy)phenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide;N-{[6-hydroxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide;N-{[6-chloro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide;N-{[5-methyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-methoxy-2-methylphenyl)carboxamide;N-([5-amino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide;N-{[5-methyl-1-(4-trifluoromethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide;N-{[5-methyl-1-(4-trifluoromethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2,6-dimethylphenyl)carboxamide;N-{[1-(4-moxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(4-hydroxy-2,6-dimethylphenyl)carboxamide;N-{[1-(4-(2-hydroxyethoxy)-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide; andN-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(3-hydroxypropyl)(2,4,6-trimethylphenyl)carboxamide.
 52. A compound according to claim 1,which is:N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2,6-dimethylphenyl)carboxamide.
 53. A compound according toclaim 1, which is:N-{[5-methyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2,6-dimethylphenyl)carboxamide.
 54. A compound according toclaim 1, which is:N-{[5-bromo-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 55. A compound according to claim 1,which is:N-{[1-(4-fluoro-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 56. A compound according to claim 1,which is:N-{[1-(4-methoxy-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.57. A compound according to claim 1, which is:N-{[5-tert-butoxycarbamyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.58. A compound according to claim 1, which is:N-{[5-dimethylamino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.59. A compound according to claim 1, which is:N-{[1-(4-hydroxy-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.60. A compound according to claim 1, which is:N-{[1-(4-(2-hydroxyethoxy)-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.61. A compound according to claim 1, which is:N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(4-dimethylamino-2,6-dimethylphenyl)carboxamide.
 62. A compoundaccording to claim 1, which is:N-{[5-diethylamino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.63. A compound according to claim 1, which is: N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-[1-(hydroxymethyl)ethyl](2,4,6-trimethylphenyl)carboxamide.64. A compound according to claim 1, which is:N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-[2-hydroxy-1-(hydroxymethyl)ethyl](2,4,6-trimethylphenyl)carboxamide.65. A compound according to claim 1, which is:N-{[5-iodo-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.
 66. A compound according to claim 1,which is: N-{[1-(4-hydroxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.67. A pharmaceutical composition comprising a compound according toclaim 1 and at least one pharmaceutically acceptable carrier orexcipient.